Project Abstract Currently we have limited therapeutic options to treat patients with advanced non- resectable, recurrent and metastatic cancer. An innate immunity-mediated anticancer immunotherapy, alone or in combination with other therapies, represents a promising novel approach. Toll-like receptors (TLRs) play a crucial role in innate immunity and inflammation. We have found that members of the TLR receptor family are expressed not only in innate immune cells but also in different cancer cells. However, only TLR5 can be activated in both breast and prostate cancer cells to induce a robust immune response, which can effectively inhibit cancer cell proliferation. Furthermore, we recently discovered that a ten-amino acid long peptide (Tf10) derived from the bacterial protein flagellin (an agonist for TLR5) is able to target TLR5 on cancer cells and inducing anti- tumor responses. I now propose to use the Tf10 peptide/TLR5 interaction in the search for and design of novel therapeutic anti-cancer agents.